Researchers , Regulators , and Sponsors Views on Pediatric ... · clinical care, addressing the unique needs of children, and streamlining regulatory approvals were suggested. Stakeholders

ARTICLEPEDIATRICS Volume 138 , number 4 , October 2016 :e 20161171

Researchers’, Regulators’, and Sponsors’ Views on Pediatric Clinical Trials: A Multinational StudyPathma D. Joseph, BPharm, MPharm, PhD, a, b, c Jonathan C. Craig, MBChB, FRACP, PhD, a, d Allison Tong, BMedSc, MPH (Hons), MM, PhD, a, d Patrina H.Y. Caldwell, BMed, FRACP, PhDa, c

abstractBACKGROUND AND OBJECTIVE: The last decade has seen dramatic changes in the regulatory

landscape to support more trials involving children, but child-specific challenges and

inequitable conduct across income regions persist. The goal of this study was to describe

the attitudes and opinions of stakeholders toward trials in children, to inform additional

strategies to promote more high-quality, relevant pediatric trials across the globe.

METHODS: Key informant semi-structured interviews were conducted with stakeholders

(researchers, regulators, and sponsors) who were purposively sampled from low- to

middle-income countries and high-income countries. The transcripts were thematically

analyzed.

RESULTS: Thirty-five stakeholders from 10 countries were interviewed. Five major themes

were identified: addressing pervasive inequities (paucity of safety and efficacy data,

knowledge disparities, volatile environment, double standards, contextual relevance,

market-driven forces, industry sponsorship bias and prohibitive costs); contending

with infrastructural barriers (resource constraints, dearth of pediatric trial expertise,

and logistical complexities); navigating complex ethical and regulatory frameworks

(“draconian” oversight, ambiguous requirements, exploitation, excessive paternalism

and precariousness of coercion versus volunteerism); respecting uniqueness of children

(pediatric research paradigms, child-appropriate approaches, and family-centered

empowerment); and driving evidence-based child health (advocacy, opportunities,

treatment access, best practices, and research prioritization).

CONCLUSIONS: Stakeholders acknowledge that changes in the regulatory environment

have encouraged more trials in children, but they contend that inequities and political,

regulatory, and resource barriers continue to exist. Embedding trials as part of routine

clinical care, addressing the unique needs of children, and streamlining regulatory

approvals were suggested. Stakeholders recommended increasing international

collaboration, establishing centralized trials infrastructure, and aligning research to child

health priorities to encourage trials that address global child health care needs.

aCentre for Kidney Research and bThe Pharmacy Department, The Children’s Hospital at Westmead, Sydney,

Australia; and cDiscipline of Adolescent and Child Health and dSchool of Public Health, The University of Sydney,

Sydney, Australia

Dr Joseph contributed to study conception and design, data acquisition, analysis and

interpretation of the data, and drafting and revising the manuscript; and Drs Caldwell, Tong, and

Craig contributed to study conception and design, reviewing the collected data, analysis and

interpretation of the data, and critical review of the manuscript. All authors approved the fi nal

manuscript as submitted.

To cite: Joseph PD, Craig JC, Tong A, et al. Researchers’, Regulators’, and

Sponsors’ Views on Pediatric Clinical Trials: A Multinational Study. Pediatrics.

2016;138(4):e20161171

WHAT’S KNOWN ON THIS SUBJECT: Conducting clinical trials

in children is complex because of safety concerns, stringent

regulatory requirements, lower prevalence of disease, and

lack of commercial interest. Recent changes in the regulatory

environment have alleviated these challenges somewhat.

WHAT THIS STUDY ADDS: This article provides stakeholder views

on mitigating the inequities by addressing children’s unique

needs, integrating trials into clinical care, streamlining regulatory

approvals, building infrastructure, relevant pediatric trials.

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JOSEPH et al

The last decade has seen major

changes in the regulatory framework

for clinical trials in children, resulting

in substantial incentivization

for industry and investigators to

rigorously evaluate new therapies

through the conduct of trials. 1 – 3

Several pediatric research networks

have also been established to

support trials in children, with

variable success. 4, 5 Despite these

advances, children all too often

remain “therapeutic orphans, ” as the

majority of medicines prescribed

for this age group have still not

been adequately tested for safety

and efficacy, and disparities exist

compared with adults and according

to income regions. 1

Trials in children are complex and

can be challenging due to the unique

requirements of this population,

safety concerns, stringent ethical

requirements, and the lack of

commercial interest. 6, 7 In low-

and middle-income countries

(LMICs), there are additional

challenges related to poverty, fear

of exploitation, and mistrust. 8, 9 The

pharmaceutical industry is perceived

as reluctant to conduct trials in

children, whereas pediatricians’

concerns regarding risks are seen as

barriers.1

The goal of the present study was to

describe the attitudes and opinions of

researchers, regulators, and sponsors

regarding the conduct of clinical

trials in children. A comprehensive

understanding of their values, beliefs,

and experiences across different

income contexts could inform local

and international strategies to

improve the number, quality, and

appropriateness of trials conducted

in children.

METHODS

The Consolidated Criteria for

Reporting Qualitative Research

framework was followed for

interviews and focus groups. 10

Respondent Selection and Practice Setting

Respondents were eligible if they

were researchers, regulators,

or sponsors involved in trials in

children. Consumers (children,

families, and the public) were

excluded. Respondents were

purposively selected to capture a

range of age, sex, income settings,

and experience in trials. Respondents

were recruited via professional

networks. A snowball sampling

strategy was also used whereby

respondents could nominate

others who could add a different or

important viewpoint. The University

of Sydney Ethics Committee

approved this study.

Data Collection

The interview guide was based

on a systematic review of trials

in children and discussion among

the study team. 1 It focused on

the challenges and strategies to

improve trials relevant to child

health (Supplemental Table 4).

From October 2013 to August 2014,

the lead author (P.D.J.) conducted

face-to-face interviews in offices

or meeting rooms or via telephone.

Respondent recruitment ceased

when theoretical saturation (ie,

when little or no new information

was being obtained from subsequent

interviews) was reached. 11, 12 We

audio-recorded and transcribed all

interviews.

Analysis

Transcripts were entered into

HyperRESEARCH version 3.5.2

software (ResearchWare Inc,

Randolph, MA). Based on grounded

theory 13 and thematic analysis, 12

the lead author (P.D.J.) coded

transcripts line-by-line and then

translated similar and different

concepts into existing or new codes,

respectively, as they emerged in the

data. Similar concepts were grouped

into themes and subthemes, and the

coding structure was revised until

all concepts relating to barriers and

enablers of trials in children were

captured. Relationships and patterns

between themes were identified

to develop a thematic schema. To

enhance the comprehensiveness and

validity of the thematic framework,

the preliminary findings were

discussed among the research team

(investigator triangulation) and

then e-mailed to all respondents,

who were given 2 weeks to include

additional viewpoints (ie, member

checking). Their feedback was coded

and incorporated into subsequent

revisions of the analytical framework.

RESULTS

Study Respondents

In total, 35 (88%) of the 40 invited

stakeholders participated. They were

from 10 countries; 20 stakeholders

were from high-income countries,

and 15 stakeholders were from

LMICs ( Table 1). Nonparticipation

was due to nonavailability or

institutional restrictions. The

duration of the interview ranged

from 20 to 70 minutes. Eight

interviews were conducted

face-to-face.

Themes

Five major themes were identified:

addressing pervasive inequities,

contending with infrastructural

barriers, navigating complex

regulatory and ethical frameworks,

respecting uniqueness of children,

and driving evidence-based child

health. These themes are described

with illustrative quotations in Table

2 and Supplemental Table 5. Figure

1 shows the conceptual relationships

among themes and subthemes.

Addressing Pervasive Inequities

Paucity of Safety and Effi cacy Data

The growth in the number of trials

in diseases specific to children was

perceived to be less than expected.

Clinicians were concerned that

children could potentially be harmed

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PEDIATRICS Volume 138 , number 4 , October 2016

due to “treatment uncertainties” and

“practicing unresearched health care”

because trials were still “skewed”

with data from the adult population.

In particular, respondents felt there

was a paucity of safety and efficacy

data in diseases with a high burden

in resource-poor settings, rare

childhood diseases, older off-patent

medicines, and younger age groups.

Knowledge Disparities

Researchers believed that they were

perceived by some pediatricians,

the community, and politicians to be

“using” children and were described

as “vampires after your blood.” Some

respondents believed that parents in

the West were “pretty informed and

educated, ” whereas researchers in

LMICs had to contend with language

barriers and lower health literacy in

parents.

Volatile Environment

The entrenched social disadvantage,

local political instability, and

corruption in certain LMICs were

offered as the main reasons for

insecurity and hesitation among

local researchers to conduct trials

in children. Historical fears were

believed to have damaged public

trust of trials involving children (eg,

the unethical trials conducted during

World War II in Germany).

Challenging Double Standards

The “double standard” of the

bureaucratic burden and regulatory

requirements to conduct trials in

children, compared with the ease

of using untested interventions in

routine clinical care, was questioned.

There was controversy regarding

the proposal of using placebos or

inferior treatments as comparators

in trials in LMICs, where the

international standard of care was

not routinely available. Regulators in

the United Kingdom and the United

States queried why it was “illegal”

to pay children anything beyond

reimbursement for trial expenses,

whereas in adult trials, it was “fair to

pay” for participation.

Ensuring Contextual Relevance

A “disconnect” between the pediatric

burden of disease and countries

in which trials were conducted

was reported by respondents.

Researchers believed “data which

are not Indigenous” may not be

relevant to local settings because of

“pharmacogenomic differences” and

variability in health care.

Market-driven Forces

Respondents believed industry

would “leverage their resources”

in trials in which there was greater

“financial reward” rather than for

“humanitarian reasons.” Clinicians

argued that most trials were focused

on diseases in adults, driven by

political and economic influences,

and the regulatory incentives for

involving children in trials only

helped to “tie the pediatric caboose

to the adult marketing train.” They

3

TABLE 1 Respondent Characteristics (N = 35)

Characteristic N (%)

Sex

Male 25 (71)

Female 10 (29)

Age group, y

<40 5 (14)

40–49 9 (26)

50–59 12 (34)

60–69 9 (26)

Country of practice

High-income countries

Australia 5 (14)

Canada 5 (14)

Finland 1 (3)

France 1 (3)

United Kingdom 3 (5)

United States 5 (14)

LMICs

India 5 (14)

Nigeria 4 (11)

Papua New Guinea 1 (3)

South Africa 5 (14)

Rolea

Researchers/cliniciansb 30 (50)

Regulatorsc 20 (33)

Sponsord 10 (17)

Specialty areaa

General pediatrics 13 (21)

Subspecialitye 46 (72)

Other 3 (5)

Clinical trial experience, y

<10 13 (37)

10–20 11 (31)

21–30 7 (20)

>30 4 (11)

a Numbers do not equal 35 because multiple categories apply to some individuals.b Researchers: academic, administrator, clinicians/pediatrician, clinical pharmacologist, investigators/researcher,

methodologist, networks/working groups, clinical trials center/clinical research facility, and trial coordinators/assistants.c Regulators: institutional review board (bioethicist, ethics committee member, ethical review bodies, ethics subcommittee/

scientifi c advisory committee member), networks/working groups, Data Safety Monitoring Board or Data Monitoring

Committee/local safety monitor, regulatory body, policy makers, and research governance.d Sponsors: academic sponsor, charitable organizations, clinical research assistants, government funding body, monitors,

pharmaceutical industry, contract research organization, and consultancy work with sponsors.e Number of respondents in subspecialties were as follows: cardiology, n = 1; clinical pharmacology, n = 2; emergency,

n = 1; endocrinology, n = 2; immunology and infectious disease, n = 8; intensive care, n = 3; hematology, n = 3; neonatology,

n = 7; nutrition, n = 1; oncology, n = 8; psychological medicine or mental health, n = 2; renal, n = 3; respiratory, n = 4; and

musculoskeletal or rheumatology, n = 1. Other: ethics, n = 1; methodology, n = 2.


JOSEPH et al 4

TABLE 2 Selected Quotes to Support Each Theme

Subthemes Illustrative Quotation

Addressing pervasive inequities

Paucity of safety and

effi cacy data

We know that children’s health professionals have a background of working without an evidence base, because that is all that they

could do up to now. (Researcher, research facility, network, United Kingdom)

Knowledge disparities As a doctor, people tell me just do whatever is good for me; he will not be able to understand the meaning of a clinical trial. He will

say, ‘are you trying to use me as, a guinea pig or something?’…So the meaning of consent is entirely different for an illiterate

patient compared with an Internet-savvy, educated one. (Researcher, trial coordinator, India)

Volatile environment And it has worsened by...the medical profession also becoming extremely defensive, because they don’t want to get into any trouble

and bad media publicity if something goes wrong. But this is where actually we really are getting hurt, especially in pediatric

research. (IRB, CRO, India)

The other challenge that one could face in Nigeria is the challenge of conducting studies in places where you have political

skirmishes. Where there are such skirmishes, it can affect research, especially if the investigator is not experienced. (Researcher,

IRB, monitor, Nigeria)

Challenging double

standards

For a very simple regimen to treat Burkitt’s lymphoma, it was being done in Malawi...the ethics committee in Nigeria refused the

protocol. Even though the drugs are cheap and affordable, it was seen as reduced effi cacy than the current standard treatment in

the country. (Researcher, pediatrician, Nigeria)

If I want to treat a child and it is not so much as here take this medicine. If I want to recruit them into a trial and give them the same

medicine, I have to give them a 20-page information sheet and go through a vast number of hoops. There seems to be double

standards which one might argue inappropriate standards for research. (Regulator, pediatrician, United Kingdom)

Ensuring contextual

relevance

Research in a developing country, it’s like a copy/paste thing from the West…a lot of money goes into it, and we just replicate

research with not many really great outcomes. (Researcher, trial coordinator, India)

I don’t do pie-in-the-sky research. I don’t have the time, to be honest. All my research, everything I prepare, and even published, has

clinical relevance…are all based on clinical need. (Researcher, IRB, regulator, South Africa)

Market-driven forces So in most cases those drugs are developed for adults because that is where the biggest need is. And now we have laws that require

us to also study those drugs in children. And that’s great. But it doesn’t mean that we’re looking carefully to study drugs for a need

for children primarily. (Researcher, pediatrician, industry sponsor, United States)

Industry sponsorship

bias

Within the physician environment, defi nitely industry-sponsored trials are seen as with a bit of bias and real question as to whether

physicians soil themselves by getting involved with industry. (Researcher, IRB, governance, Canada)

So even a high-quality investigator-initiated study doesn’t change any market authorization for children or even lead to include other

new fi ndings if necessary, unless the pharmaceutical company who has the market authorization for this product is willing to then

submit the data for regulatory approval. (Researcher, pediatrician, IRB, Finland)

Dissuaded by

prohibitive costs

Investigator-initiated trials were sometimes possible here like the neonatal trials around caffeine for apnea. But they all cost $5

million each to answer 1 question, and so there’s no more money in the public arena to sponsor trials that are that expensive.

(Researcher, pediatrician, academic, Canada)

There are not a lot of rewards for the faculty who are involved, particularly when there are small numbers of patients who would be

enrolled at any 1 site to warrant their spending time, very considerable time on putting through the consent forms, the contracts,

the IRB approvals and then looking for the 1 or 2 patients who they may be able to involve. (Researcher, pediatrician, industry

sponsor, United States)

Contending with infrastructural barriers

Overwhelming

resource constraints

You have brilliant ideas, but the brilliant ideas at the best they end on the desktop because of the lack of funding. Because…issues

relating to children tend to be culturally very last on the priority list…So where we really have the big need is how to get funding

for the investigator-initiated studies. (Researcher, IRB, monitor, Nigeria)

We have turned downed studies on occasions where we didn’t have the resources to carry them out. (Researcher, IRB, South Africa)

Dearth of pediatric trial

expertise

I can’t tell you the number of meetings that I have been in where someone said GCP and somebody goes, ‘what’s that?’ ‘Good Clinical

Practice.’ First of all, we have no real sticks, we have possibly some carrots but we’re sort of neutral on ensuring in a satisfactory

fashion that investigators and their staff are qualifi ed and suffi ciently maintained skills to carry out trials. (Researcher, IRB,

governance, Canada)

When companies submit proposals for pediatric clinical trials for regulatory approval, they don’t get an answer. Because nobody is

really able to assess the appropriateness of the study. (Researcher, pediatrician, IRB, Finland)

They are not robust so the science behind what gets submitted is sometimes not good quality; so, people often have not thought

about…sample size calculations, recruitment, the feasibility of the study and…the practicalities of actually conducting the trials.

(Researcher, pediatrician, IRB, Australia)

Traversing logistical

complexities

We have some issues such as electricity or power supply which is not very regular, and storage facilities to keep specimens are

a challenge because of erratic power supply. And therefore if you are going to conduct clinical trials here, you would need an

alternative source of power to ensure that biospecimens and other items are kept properly. (Researcher, Nigeria)

So if you need to get samples for central review or for collaborative studies they have to arrive within 24 to 48 hours. That can be

logistically impossible from Australia. (Trial coordinator, trial center, Australia)

Navigating complex regulatory and ethical frameworks


PEDIATRICS Volume 138 , number 4 , October 2016 5


“Draconian” oversight Some of the regulations around that are quite stringent and that we can’t follow to the letter at the moment because it’s just

impractical. For instance, it says the Minister has to provide consent for every child that participates in a study. (Researcher,

pediatrician, South Africa)

I mean the 17-page sort of consent forms outlining every conceivable risk is counterproductive to good clinical practice, it’s

counterproductive to good science, it’s counterproductive to moving things forward and making things better for everyone.

(Researcher, regulator, government sponsor, Australia)

Ambiguous

requirements

One area of uncertainty seems to be the defi nitions of key terms such as minimal risk and minor increase over minimal risk, in the

pediatric context. (Regulator, IRB, governance, United States)

There are certain South American countries that just won’t allow research with a placebo, and there are countries right next door

that do. So it’s whatever the local laws and regulations govern. (Researcher, pediatrician, industry sponsor, United States)

Fear of exploiting the

vulnerable

In a developing world context, there’s a greater potential for exploitation and because in a way they’re a vulnerable population;

socioeconomically, they’re vulnerable, from a point of view of levels and standards of education they’re vulnerable, from a point

of view of access to care their vulnerable…the reduced capacity for authorities and ethics committee to deal with these complex

issues. (Researcher, pediatrician, South Africa)

Excessive paternalism

and unwarranted

exclusion

If we are convinced of…our basic research that’s Phase I, Phase II studies and that we’ve done this safely, crossed our ‘t’ and dotted

our ‘i’ and you know it’s safe. I don’t think we need to go adults fi rst and then children...all studies that are safe should be offered

to children and adults. This artifi cial cutoff that we are going to do it in adults fi rst then children should not exist. (Researcher, IRB,

regulator, South Africa)

Precariousness of

coercion versus

volunteerism

They may offer treatment that is otherwise unreachable by the children in this area, too expensive or not present at all. It may bring

equipment to the centers such as laboratory, x-ray, and ultrasound whatever is needed for the trial that remains there after the

trials. But these are ethically very diffi cult questions. Because it is possible that this indirect benefi ts that benefi t the whole health

care system…may lead to a situation where children are then allowed to participate in…trials for reasons that are not directly

for the benefi t of themselves but for the benefi t of the society. (Researcher, pediatrician, IRB, Finland)

Respecting uniqueness of children

Embracing pediatric

research paradigms

Regulatory agencies need to move away from a very narrow interpretation of indications in terms of pediatric studies…right now

so much of it’s still based on the adult indications and the pediatric-intended indications being similar. That’s certainly not always

the case; for example, sildenafi l is used in adults to treat erectile dysfunction and it’s used in premature neonates for pulmonary

hypertension. Certainly, those 2 indications are very different as are the populations…So we’re moving toward an assessment

of effect as a way to bridge data between adults and children…And also moving away from trying to prove in some cases that

the disease processes are substantially similar, …asthma is asthma, but the disease process is very different. (Researcher,

pharmacologist, United States)

But now the trend has been turning. It probably started with the orphan regulations in Europe where it very quickly became clear

that there are no way you can make big clinical trials in rare diseases…optimally, pediatric trials should use methods that are

designed for small size clinical trials. (Researcher, pediatrician, IRB, Finland)

And it is very dangerous to have a comparator that is an unproven treatment and children are exactly in this position because many

of the pediatric treatments even if they are considered current choice of treatment, have not been well documented. (Researcher,

pediatrician, IRB, Finland)

Considering child-

appropriate

approaches

Sometimes we get protocols that are not designed with children in mind so that the assessment periods are too tightly scheduled, or

the number of assessments is not appropriate for children. So they’ve looked at adult studies and tried to just sort of adapt that

to children by just scaling down the dose. And they haven’t really thought…kids aren’t going to come in for that many visits and

they’ve got school and they’ve got exams. And they’ve got days where they just don’t feel like being poked and prodded and they’re

just not going to comply. And the protocols are not always written with that fl exibility that’s required for working with children in

mind. (Trial coordinator, trial center, Australia)

Facilitating family-

centered

empowerment

In the oncology arena, the positive aspects are that the parents are always very enthusiastic and very supportive. So, they see it as

an opportunity for their child, and they’re very engaged so we don’t have problems with compliance and follow-up because the

parents want to do the right thing and want to contribute. (Trial coordinator, trial center, Australia)

I think parents, children, and young people need to be at the center of research and that needs to be nurtured. When people are

familiar with clinical trials terms, they can be very productive, but unless they’re supported, it can be a very bruising journey that

wastes a lot of time. So there needs to be specifi c support for children, parents, and young people that best works with networks.

(Researcher, regulator, industry consultant, United Kingdom)

Driving evidence-based child health

Promoting research

advocacy

Use all international forum and collaborations to raise awareness, to show success, demonstrate projects that it is feasible and that

it is ethical and it is safe for the participant to be in a clinical trial…maybe using international platforms such as WHO, maybe

others to engage more children, families, clinicians and researchers across the world. (Researcher, pediatrician, academic,

Canada)

Creating and seizing

opportunities

The most feasible way today would be in the form of building infrastructure where you can have networks with people who are full-

time professionals assisting in the local running of the clinical trials. (Researcher, pediatrician, IRB, Finland)

They have been very successful because of a top-down funding model by the NHS (National Health Service) to get the Medicines for

Children Research Network going. And they have accomplished a lot of success. (Researcher, pediatrician, academic, Canada)

TABLE 2 Continued


JOSEPH et al 6


Supporting best

practice

Up to 80% or 90% of pediatric clinical trials are at an uncertain or high risk of bias when it to comes to randomization sequence,

allocation concealment, blinding of the intervention of the outcome measurers, attrition, and second outcome reporting. So bias

is a big threat to the validity and ineffi ciency and impact of trials, and so we need to start reducing research waste. (Researcher,

pediatrician, academic, Canada)

All research should be demand-driven, by people who live and work in those countries, by Ministries of Health, by institutions of

academia or science in those countries. I’ve seen it a lot, but I don’t believe that outside institutions should come and just set up

trials with minimal collaboration… there needs to be very good…nontrial evidence, epidemiologic evidence showing the burden

of the problem. (Researcher, pediatrician, DSMB, Papua New Guinea)

Improving access to

treatment

It …would be unethical not to study the medicines in the children of resource-limited country if they need the medicines and if they

are used anyway. (Researcher, pediatrician, IRB, Finland)

If it was performance indicator of a CEO of a hospital or other things, that would be seen it was desirable that people involve in

clinical trials. Funding would fl ow to it in a way that it doesn’t now…it needs to be embedded more at the center of clinical care.

(Trial coordinator, IRB, government sponsor, Australia)

Prioritizing research

productivity

More trials to do with targeting where the burden of disease is. It’s always a balancing act. Pediatrics has its fair share of rare

diseases in terms of genetic disorders and other things that only occur in children. You wouldn’t want to see all the resourcing

going toward diseases like diarrhea management, middle ear infection. (Trial coordinator, IRB, government sponsor, Australia)

Pooling of resources, making sure resources are not focused in rich countries. They need to be universally available…Sexy things

get the funding…where they can get publicity…there needs to be an appraisal of what research we are doing; what bang for

our buck we are getting;…We know the burden of disease…we need to prioritize the research in the right way! (Researcher, IRB,

regulator, South Africa)

CEO, chief executive offi cer; CRO, contract research organization; DSMB, Data Safety Monitoring Board; IRB, institutional review board; WHO, World Health Organization.

TABLE 2 Continued

FIGURE 1Thematic schema of challenges and enablers of clinical trials in children.



surmised that it had been “a happy

marriage between industry and

regulators” to conduct trials in

children with a large sample size as a

“preauthorization marketing tool.”

Industry Sponsorship Bias

Industry-sponsored trials were

noted to be almost always

multinational and of higher

quality because of adherence to

regulatory standards for obtaining

marketing authorization. In contrast,

investigator-initiated trials were

deemed to be of “poor quality, ”

“curiosity-driven, ” or for academic

promotion. Clinicians suspected that

investigators reluctantly participated

in industry-sponsored trials so

that they could “pay the rent”

and subsidize their own research.

Industry sponsors believed that the

majority of industry “get tainted

in that stigma” by the minority of

pharmaceutical companies who

conduct research unethically. They

believed the position “damned if they

do and damned if they don’t” involves

children from LMICs in trials.

Dissuaded by Prohibitive Costs

The “manifold costs” of regulatory

oversight were perceived as

a “double-edged sword” for

investigators who had to conduct

trials “on shoestring budgets or no

budgets.” Trials in children were

perceived to be a “financial risk” to

industry because of the small pool

of eligible patients, longer follow-up,

and the increasing site costs. Industry

sponsors were polarized regarding

the perception that they were

“shifting” research to the LMICs

where it was a “cheaper” option.

Contending With Infrastructural Barriers

Overwhelming Resource Constraints

Researchers stated that “funding

was the bane of doing research” in

children, as pediatric trial facilities

and resources were scarce, especially

in disadvantaged settings.

Dearth of Pediatric Trial Expertise

Respondents noted a critical lack

of expertise in pediatric trials.

Some researchers from LMICs

acknowledged that they developed

expertise from participating in

industry-sponsored trials. Many felt

that clinicians required appropriate

rewards and “career pathing” to

enhance participation in trials.

Traversing Logistical Complexities

All respondents had to confront

logistical complexities such as

shipping samples overseas. Logistical

difficulties were particularly

challenging in LMICs. For example,

researchers in Nigeria had to

contend with electricity disruptions,

unreliable telecommunication, and

difficulty in following up respondents

who frequently relocated.

Navigating Complex Ethical and Regulatory Frameworks

“Draconian” Oversight

Researchers believed that

“draconian” ethical and regulatory

oversight was a barrier to

conducting trials in children.

Navigating the long, heterogeneous,

and duplicative process of

obtaining multiple approvals was

considered “cumbersome, ” and the

informed consent requirements

were described as onerous and

impractical. Some respondents

were frustrated that research funds

were wasted on “unreasonable

bureaucracy, ” while acknowledging

that without a “robust governance

and safety system we would

prejudice our research.”

Ambiguous Requirements

Many felt that the variability in the

quality of ethical deliberations and

“ambiguous” trial guidelines “drives

people crazy” and potentially leads to

“unequal protection.”

Fear of Exploiting the Vulnerable

Some respondents believed that

children in LMICs were exploited

to address the health care needs

primarily of wealthy nations. Ethics

committee members opposed

“exposing children to inappropriate

level of research risk absent of

any prospective direct benefit”

(eg, inserting a central line for

placebo administration). The new

mandatory requirement of audio-

visual consent in India was believed

to protect respondents, although

some considered this requirement

to be excessive and could stigmatize

adolescents who preferred to be

de-identified.

Excessive Paternalism and Unwarranted Exclusion

Researchers and sponsors believed

that parents and regulators had

“paternalistic attitudes” and were

“overcautious” about including

children in trials. However, some

argued that excluding children was

discriminatory because “the way

we should protect children is not

from research, but through research.”

Researchers reasoned that ethics

committees and guidelines were

there to protect children from

“unreasonable, potential risk.”

Some believed that it was easier to

justify trialing medicines in neonates,

in whom there is limited or no

clinical practice evidence,

than trialing treatments that are

currently used in children

without evidence.

Precariousness of Coercion Versus Volunteerism

Researchers were uncertain

about the morality surrounding

investigator and parent’s inducement

to participate in trials, particularly

in the context of LMICs. Industry

sponsors maintained that the

amount of reimbursement could

not be universally standardized

and should be reflective of

the economy, as payment of

disproportionately high amounts

of reimbursement could unduly

influence participation.


JOSEPH et al

Respecting Uniqueness of Children

Embracing Pediatric Research Paradigms

Respondents advocated for

stakeholders to “embrace

pediatric paradigms” and consider

the “uniqueness” of children

regarding treatment response,

disease pathophysiology, and

expression. Clinicians prioritized

impact on quality of life and long-

term neurocognitive outcomes.

Respondents recommended novel,

pragmatic trial designs for small

populations of rare diseases in

children.

Considering Child-appropriate Approaches

Researchers and ethics committee

members thought that industry

neglected child-specific issues

when designing protocols.

Respondents proposed that

protocols be developed to include

child-specific considerations

such as microanalysis techniques

that require smaller volumes of

blood. They recommended a child-

friendly research environment with

distraction therapies, and using

pictures or audio-visual aids and

plain language to explain trials.

Some suggested that clinical visits or

assessments should be scheduled to

minimize interference with school

attendance.

Facilitating Family-centered Empowerment

Involving families in setting child

health care research priorities,

as well as the designing and

conducting of trials, was proposed

by researchers and regulators. The

clinical team highlighted that when

“recruiting a child, you are recruiting

the whole family.” In the United

Kingdom, families and children

involved in trial networks have

lobbied to have trial results provided

to respondents.

Driving Evidence-based Child Health

Promoting Research Advocacy

Although “great strides” in benefits

of children’s participation in trials

was recognized, further behavioral

and cultural shifts through a massive

awareness campaign was deemed

essential. The ethical case that

“children deserved evidence-based

care, ” the economic justification of

return on investment by health care

cost savings, and involving families to

obtain “public acceptance” and policy

makers’ support were encouraged.

Creating and Seizing Opportunities

Proponents of trials in children

encouraged global “societal

commitment” to dedicate funds

and attract investment in pediatric

trials. Respondents believed that

strong networking opportunities

contributed to the success of trials

in pediatric oncology. Researchers

from LMICs welcomed opportunities

for participation in international

trials. They advocated for research

to improve the health system and

philanthropic investment to build

local trial and health care capacities.

Supporting Best Practice

Respondents supported the

development of consensus trial

regulations and resources that could

be adapted to local contexts. They

believed that it would be “utopia”

to have 1 “amalgamated” national

ethical review process. However,

some regarded this scenario as

a “double-edged sword” because

a central ethical review would

eliminate the inherent quality control

provided by multiple reviewers.

Many encouraged collaboration

and sharing of expertise, and

they emphasized the need for a

centralized trials infrastructure with

research “intra-operable tools” to

support a range of study designs.

Improving Access to Treatment

Trial participation gave children

the opportunity to access new

or better treatments that may

otherwise be “unreachable, ”

expensive, or unavailable. Thus,

respondents advocated for trials

to be embedded in clinical care.

They endorsed harmonization and

augmentation of regulations and

stronger partnerships between

researchers, regulators, and

industry to support well-

designed developmental

pipelines for therapeutic agents

for children. More efficient

dissemination, translation, and

implementation of pediatric

research into practice and policy

were encouraged.

Prioritizing Research Productivity

Multi-stakeholder collaboration

to improve trials in child health

care globally and reduce research

waste was deemed crucial.

Prioritization of child health

care needs based on analysis of

epidemiologic or trial registries

data was recommended. Burden

of disease, balanced by scientific

opportunities in rare diseases, was

considered important to justify

expenditures in prioritizing funding

universally.

DISCUSSION

A broad range of stakeholders

involved in the conduct of trials in

children recognized that much had

been done to promote trial-informed

clinical care of children but that

large-scale cultural and behavioral

changes, coupled with substantial

infrastructural enhancement,

were still required to promote the

conduct of more trials that were

relevant and of high quality. They

believed that there was still a

scarcity of child health care safety

and efficacy data, most notably

in LMICs, child-specific diseases,

neonates, off-patent medicines, and

child-appropriate formulations.

Challenges and specific pediatric

disparities were believed to arise

from fears of harming children,



political and economic influences,

lack of resources for pediatric trials,

and the bureaucratic regulatory

framework. Global multi-stakeholder

collaboration, integration of trials

as part of clinical care, sustainable

centralized trials infrastructure,

harmonization of regulatory

approvals, and alignment of the

pediatric research agenda through

analysis of trial registries and

epidemiologic data were believed to

enhance global capacities to conduct

pediatric trials.

A recent systematic review of

stakeholder views of trials in children

in LMICs identified challenges related

to social disadvantages, idiosyncratic

cultural beliefs, and historical

disempowerment, with community

engagement as the main enabler. 9

In our study, more challenges were

identified by respondents in LMICs,

where few trials are conducted

despite the enormous pediatric

disease burden. Some respondents

were concerned about safety and

exploitation of children, whereas

others maintained that trial

participation protects children from

harm caused by non–evidenced-

based health care. 14, 15

In addition to the frustration

engendered by what was regarded

as shortcomings in the technical

capacity of ethics committees

and ambiguities in the regulatory

requirements, 16 – 18 researchers

in the present study questioned

the legitimacy of being explicit

about treatment uncertainties

and enrolling children in trials as

opposed to the ease of giving the

same untested treatment in routine

clinical practice. Some felt that it

was unethical and discriminatory

not to involve children in

trials. Stakeholders supported

harmonizing and expediting ethical

review and developing local and

international standards. They

believed this approach would

reduce duplication and improve

efficiency of ethical approval. 19, 20

Professional stakeholders were

polarized regarding the current

regulations forbidding payment

to children for participation in

trials. 21

Stakeholders encouraged regulators

worldwide to adopt appropriate

regulations for the conduct of

trials in children. They recognized

that market exclusivity incentives

supporting patent protection

were not designed to meet the

current needs of children, and this

observation was corroborated in a

recent examination of drugs granted

exclusivity. 22 Stakeholders endorsed

improved regulations and incentives

addressing child-specific therapeutic

needs, off-patent medicines, and

rare childhood diseases. 23, 24 To

accommodate the low disease

prevalence in children, innovative

and optimum methods were

suggested. 25– 27

Amalgamated government and

philanthropic investments with

strengthened multi-stakeholder

partnership were regarded

as necessary to improve drug

development for pediatric

use. Stakeholders supported

multicenter collaborative trials

and open disclosure of trial results

through registries to reduce

research waste and increase

clinical benefit. Investment in a

global governance framework of

registries was encouraged to assist

expedient availability, translation,

and implementation of trial

results. 28 Incorporating analysis

of epidemiologic and registries

data to inform clinical research

needs in children was supported,

and integrating trials as part of

routine clinical care was considered

essential to bring interventions

to the bedside in a sustainable

manner.

Greater investment in training and

resources is urgently required to

help progress investigator-

initiated trials to the regulatory

standards that are required to

inform labeling changes of medicines

for use in children. Guidance and

standards to improve pediatric

trial design, conduct, and reporting

are recognized as vital, with

some initiatives underway. 4, 29, 30

Establishing networks to

collaborate and support trials was

deemed essential by stakeholders.

Investing in a centralized trial

infrastructure with sustainable

funding that could support

different studies was considered

crucial to promote more high-

quality trials in children. This

infrastructure has been shown

to be beneficial, as illustrated

in the highly successful UK

Medicines for Children Research

Network. 31

Our international study highlights

a wide spectrum of opinions

of pediatric trial experts and

decision-makers across different

income and health care settings.

We applied member checking to

ensure that the analysis reflected

the range and depth of the data

collected. Our study outlines

those recommendations that will

be of interest to all stakeholders,

including policy makers, to enable

more high-quality trials primarily

by making more explicit and

informed decisions concerning child

health research priorities ( Table 3).

However, there are some potential

limitations. The transferability

of the findings to countries that

were not included in our study

is uncertain. We recommend

extending similar research to other

countries that have different health

systems, regulations, culture, and

resources.

CONCLUSIONS

Stakeholders acknowledge

that changes in the regulatory

environment have encouraged


JOSEPH et al 10

TABLE 3 Implications for Practice and Policy to Address Barriers and Inequities

Key Issues Recommendations or Suggested Research and Policy Priorities (Examples and Initiatives Underway)

Advocate for trials in

children

• Campaign for children’s participation in trials, using both ethical and economic justifi cation strategies

• Analyze health, epidemiologic, and registries data to inform clinical research needs in children

• Align the academic, pharmaceutical sponsor, and policy maker’s agendas to prioritize research in response to child health needs

through a multinational consortium

• Invest and direct prioritization of trials in children from government

• Incentivize trials of off-patent medicines (eg, priority list of off-patent medicines developed by the US Pediatric Trials Network 32)

• Improve initiatives to study rare diseases (eg, FDA priority review voucher, 33 International Rare Diseases Research Consortium 34)

• Encourage philanthropic approaches to conduct high-quality research that changes pediatric labeling

• Provide better incentives to encourage clinicians’ participation and enthusiasm

Strengthen and develop

pediatric trial capacity

• Invest in sustainable centralized trial infrastructure, including dedicated management team of a statistician, research nurse, data

manager, and pharmacist to support investigators

• Establish networks with sustainable funding to collaborate and support trials in children, especially nonindustry-sponsored trials

(eg, Medicines for Children Research Network 31)

• Develop standards and guidance on trial design, conduct, and reporting (eg, valid child health outcomes including child-reported

outcomes), explicit defi nitions (eg, minimal risk, adequate sample size), selection of appropriate comparators, reduction of risk of

bias (eg, StaR Child Health, 35 Toronto Outcomes Research in Child Health, 36 Enhancing Research Impact in Child Health, 37 Standard

Protocol Items for Randomized Trials–Children, 38 Consolidated Standards of Reporting Trials–Children39)

• Invest in training and standards for consistency and high-quality review of ethics applications

• Develop guidelines for data safety monitoring committees

• Implement programs to audit the conduct of trials at sites

Mitigate disparities in

LMICs

• Increase research and development investment to encourage trials in LMICs

• Build expertise in LMICs by encouraging research collaborations with investigators from high-income countries

• Share trial resources of high-income countries for adaptation to local contexts

• Advocate for philanthropic investment to build local trial and health care capacity

• Encourage operational research (advanced analytical techniques) on improving practices in these diffi cult contexts

• Invest in prevention and curative health services and research to address some of the neglected health burdens

• Promote health and health education of the community

• Encourage sponsor provision of ongoing supportive medical care posttrial and ancillary care to siblings and other family members

Enhance regulatory

frameworks

• Adopt pediatric regulations and incentives globally to encourage pharmaceutical industry to trial medicines in children (eg, the US

and European Union regulations)

• Improve pediatric regulations and incentives to encourage trials in child-specifi c diseases, including trials of off-patent medicines

(eg, Pediatric Trials Network initiatives) 32

• Establish a global-level pediatric medicines regulatory framework under the leadership of the World Health Organization to regulate

and harmonize country of trials conduct, transferability of results, availability of medicines, and improve medicine access and

reimbursement strategies (eg, TransCelerate 40 initiative)

• Create an international network of regulators to manage the regulatory requirements and provide support for less-experienced

regulators

• Develop a log of trials to prevent duplication and identify gaps (eg, enprEMA, 41 Medicines for Children Research Network, Global

Research in Pediatrics 42 initiatives)

Improve evidence-base

practice

• Encourage multicenter collaborative trials to reduce research waste

• Develop good referral network among pediatric clinicians to enhance recruitment

• Conduct trials of more economically feasible treatment modalities for LMICs, where appropriate

• Promote ongoing supplies of successful interventions to participants, while expediting regulatory approvals of pediatric labeling

• Invest in developing formulation of medicines appropriate for children in all income regions (eg, suspensions)

• Review medicine reimbursement strategies to improve access of medicines addressing pediatric needs

• Embed clinical research as part of routine clinical care and in disease-specifi c registries (eg, Key Performance Indicator of

organization to involve children in trials)

• Invest in a governance framework of registries to address the evidence gaps in children and monitor expedient availability of trial

results

• Invest in funding for translation and implementation of effective interventions

Embrace child-appropriate

approaches

• Design protocols around pediatric needs with consultation and partnering with the academic, practicing community, and families

(eg, United Kingdom, Young Peoples Advisory Group, 43 International Children’s Advisory Network) 44

• Develop guidelines to engage children and parents in setting priorities, designing and conducting trials (eg, feasibility and selection

of patient-reported outcomes, review of consent forms, scheduling appointments)

• Adopt child-appropriate strategies such as reducing pain and discomfort of painful invasive procedures (eg, distraction techniques

such as DVDs)

• Develop alternative robust strategies to monitor compliance in children (eg, devices that can monitor use)

• Further research to develop guidelines on adequate pediatric decision-making (assent)

• Further research regarding payment to children for participating in optional research that does not offer direct benefi t for the child

• Provide patient-specifi c results sheet to families and children who participated



more trials in children to be

undertaken, but they contend that

inequities and political, regulatory,

and resource barriers still exist.

Embracing unique pediatric needs

and creating a culture of embedding

trials as part of routine clinical care

are recommended. International

collaboration, sustainable

centralized pediatric clinical

trials infrastructure, development

of pediatric trial expertise, and

alignment of research to child

health care priorities are suggested

to encourage more high-quality,

appropriate trials that address

the health care needs of children

globally.

ACKNOWLEDGMENTSThe authors thank the stakeholders

who shared their perspectives in the

study.

11

ABBREVIATION

LMICs: low- and middle-income

countries

DOI: 10.1542/peds.2016-1171

Accepted for publication Jul 22, 2016

Address correspondence to Pathma D. Joseph, BPharm, MPharm, PhD, The Pharmacy Department, The Children’s Hospital at Westmead, Corner of Hawkesbury Rd

and Hainsworth St, Westmead, NSW Australia 2145. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2016 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.

FUNDING: Supported by a National Health and Medical Research Council Postgraduate scholarship (1039338).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

COMPANION PAPER: A companion to this article can be found online at www. pediatrics. org/ cgi/ doi/ 10. 1542/ peds. 2016- 2150.

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DOI: 10.1542/peds.2016-1171 originally published online September 30, 2016; 2016;138;Pediatrics

Pathma D. Joseph, Jonathan C. Craig, Allison Tong and Patrina H.Y. CaldwellMultinational Study

Researchers', Regulators', and Sponsors' Views on Pediatric Clinical Trials: A

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DOI: 10.1542/peds.2016-1171 originally published online September 30, 2016; 2016;138;Pediatrics

Pathma D. Joseph, Jonathan C. Craig, Allison Tong and Patrina H.Y. CaldwellMultinational Study

Researchers', Regulators', and Sponsors' Views on Pediatric Clinical Trials: A

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by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397. the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2016has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it


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Researchers , Regulators , and Sponsors Views on Pediatric ... · clinical care, addressing the unique needs of children, and streamlining regulatory approvals were suggested. Stakeholders